Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis

Abstract

The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 ( CHI3L1 ) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels ( P = 7.6 × 10 −6 and coefficient = 36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels ( P = 2 × 10 −9 and coefficient = −9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 ( P = 9.9 × 10 −6 and coefficient = −13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females ( P = 1.6 × 10 −7 and coefficient = −10.08) than males ( P = 0.0021 and coefficient = −9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.

3D Deformation Patterns of S Shaped Elastic Rods as a Pathogenesis Model for Spinal Deformity in Adolescent Idiopathic Scoliosis

“…Adolescent idiopathic scoliosis (AIS) manifests as a three-dimensional (3D) deformity of the spinal column that occurs around puberty. Several factors such as genetics 1,2 , biomechanics 3 , morphology of the vertebral bones, intervertebral disc, and muscle physiology 4–9 , hormones 10,11 , environmental factors 12,13 , and neural system deficiencies 14,15 are considered as the underlying cause of the spinal deformity in AIS. While each of these factors explained part of the pathogenesis of this disease, none have proved to be its main or primary cause.…”

The role of the Chitinase 3-Like 1 (CHI3L1) genes in the preeclampsia pathophysiology

“…Dina Nada et al investigated the relationship of circulating YKL-40 levels and CHI3L1 variants with the risk of progression of scoliosis to spinal deformity in adolescent idiopathic scoliosis. It has been shown that the rs880633 polymorphism of the CHI3L1 gene is positively correlated with high YKL-40 levels and is protective against spinal deformity 14 . Huang et al examined the polymorphisms of the CHI3L1 gene in patients with hepatocellular cancer and found a high rate of CHI3L1rs880633 polymorphism in patients with hepatocellular cancer 15 .…”